Activating mutations in KRAS represent the most frequent pathologic driving force among the three protein isoforms of RAS (K-, N- and H-RAS). KRAS mutations are present in approximately 30% of tumors, and at even higher frequencies in cancers of the pancreas, lung, thyroid gland, colon, and liver. In pancreatic ductal adenocarcinomas (PDAC), one of the most lethal cancers with 5-year survival rates of less than 5%, activating KRAS mutations are found in more than 90% of the tumors [2]. Moreover, these mutations have been causally linked to the initiation and progression of PDAC [3, 4]. In general, KRAS mutations are associated with poor prognosis and treatment resistance of human tumors [5]. For example, KRAS-mutant lung and colon cancers are refractory to both small molecule EGFR inhibitors and antibodies that target overexpressed EGFR [6]. Thus, patients with KRAS mutations are non-responsive to EGFR-targeted therapies, further limiting their therapeutic options.
KRAS is a membrane-bound signaling protein that transmits growth factor receptor (such as EGFR) signals to downstream pathways, such as MAPK, PI3K and others. KRAS cycles between an active, GTP-loaded form and an inactive, GDP-bound state. Upon activation by growth factor signaling, KRAS guanidine exchange factor (GEF), a protein called SOS1, promotes the GTP-loading and thus activation of KRAS. The KRAS-GDP to KRAS-GTP transition that is catalyzed by SOS1 represents the rate-limiting step of this cyclic reaction[7]. Oncogenic mutations in KRAS are typically point mutations that stabilize the active, GTP-bound state of KRAS.
Despite the insights into the mechanism of KRAS and its pathologic mutations, the development of targeted inhibitors of KRAS for therapeutic benefit has been elusive and remains a formidable challenge [8, 9, 10, 11, 12, 13, 14 and 15].